Activated factor X stimulates atrial endothelial cells and tissues to promote remodelling responses through AT1R/NADPH oxidases/SGLT1/2.
Autor: | Fakih W; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France., Mroueh A; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France., Gong DS; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France., Kikuchi S; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France.; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Pieper MP; Boehringer Ingelheim Pharma GmbH & Co. KG, Global Cardio-Metabolic Diseases, Birkendorfer Strasse 65, 88397 Biberach, Germany., Kindo M; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Mazzucottelli JP; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Mommerot A; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Kanso M; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Ohlmann P; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Morel O; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France.; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France., Schini-Kerth V; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France., Jesel L; University of Strasbourg, UR 3074, Translational Cardiovascular Medicine, Biomedicine Research Center of Strasbourg, 1 Rue Eugène Boeckel, 67000 Strasbourg, France.; Cardiology Department, Strasbourg University Hospital, 1 place de l'Hôpital, 67000 Strasbourg, France. |
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Jazyk: | angličtina |
Zdroj: | Cardiovascular research [Cardiovasc Res] 2024 Sep 02; Vol. 120 (10), pp. 1138-1154. |
DOI: | 10.1093/cvr/cvae101 |
Abstrakt: | Aims: Atrial fibrillation (AF), the most common cardiac arrhythmia favouring ischemic stroke and heart failure involves left atrial remodelling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodelling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. Methods and Results: AECs collected from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-β-gal) activity. In AECs, FXa increased ROS formation, senescence (SA-β-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-β and collagen-1/3a) and pro-remodelling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which were prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodelling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. Conclusion: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodelling and pro-fibrotic responses in AECs and human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodelling and the progression of atrial fibrillation substrate. Competing Interests: Conflict of interest: S.K. has received a grant from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad. O.M. declared grants from AstraZeneca, Medtronic and Boehringer Ingelheim and V.S.-K. from Boehringer Ingelheim, Nugerontix Limited, and Servier. M.P.P. is an employee of Boehringer Ingelheim. The other authors have nothing to disclose. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
Databáze: | MEDLINE |
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